Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

Abstract

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR -mutant non-small cell lung cancer (NSCLC), is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition (EMT) transcription factor SLUG to directly repress pro-apoptotic BMF , limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1 , all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients. Kurppa et al. show that YAP activation mediates resistance to combined EGFR/MEK inhibition by inducing dormancy in non-small cell lung cancer cells. Targeting the YAP pathway, in part by using a newly developed covalent TEAD inhibitor, promotes apoptosis of the dormant therapy-resistant cancer cells.